Structure and allosteric activity of a single-disulfide conopeptide from Conus zonatus at human α3ß4 and α7 nicotinic acetylcholine receptors.

Conopeptides are neurotoxic peptides in the venom of marine cone snails and have broad therapeutic potential for managing pain and other conditions. Here, we identified the single-disulfide peptides Czon1107 and Cca1669 from the venoms of Conus zonatus and Conus caracteristicus, respectively. We observed that Czon1107 strongly inhibits the human α3ß4 (IC50 15.7 ± 3.0 µm) and α7 (IC50 77.1 ± 0.05 µm) nicotinic acetylcholine receptor (nAChR) subtypes, but the activity of Cca1669 remains to be identified. Czon1107 acted at a site distinct from the orthosteric receptor site. Solution NMR experiments revealed that Czon1107 exists in equilibrium between conformational states that are the result of a key Ser4-Pro5cis-trans isomerization. Moreover, we found that the X-Pro amide bonds in the inter-cysteine loop are rigidly constrained to cis conformations. Structure-activity experiments of Czon1107 and its variants at positions P5 and P7 revealed that the conformation around the X-Pro bonds (cis-trans) plays an important role in receptor subtype selectivity. The cis conformation at the Cys6-Pro7 peptide bond was essential for α3ß4 nAChR subtype allosteric selectivity. In summary, we have identified a unique single-disulfide conopeptide with a noncompetitive, potentially allosteric inhibitory mechanism at the nAChRs. The small size and rigidity of the Czon1107 peptide could provide a scaffold for rational drug design strategies for allosteric nAChR modulation. This new paradigm in the "conotoxinomic" structure-function space provides an impetus to screen venom from other Conus species for similar, short bioactive peptides that allosterically modulate ligand-gated receptor function.

Comparison of ropivacaine (0.2%) with or without clonidine 1 µg/kg for epidural labor analgesia: A randomized controlled study.

BACKGROUND AND AIMS: The aim is to determine the effect of addition of clonidine to ropivacaine for epidural labor analgesia with regard to onset of analgesia, duration of analgesia, neonatal outcome, and quality of analgesia. MATERIAL AND METHODS: A total of 60 term parturients of the American Society of Anesthesiologists Grade I and II with uncomplicated pregnancy, vertex presentation, posted for on-demand epidural labor analgesia after informed consent were divided in two groups. Group R (n = 30) patients received 10 ml solution comprising 0.2% ropivacaine. Group RC (n = 30) patients received a total of 10 ml of 0.2% ropivacaine and clonidine 1 µg/kg. Characteristics of the block, onset and duration of analgesia, and total analgesic requirements were noted. Pain and overall satisfaction scores were assessed with a 10-point visual analog scale. Mode of delivery and neonatal APGAR scores were recorded. RESULTS: Maternal demographic characteristics were comparable between the groups. Addition of clonidine to ropivacaine shortened the onset and prolonged the duration of analgesia with decrease in ropivacaine requirement in Group RC. There was a significant difference between the two groups regarding visual analog score and quality of analgesia, which was better in Group RC. There were no significant differences between the two groups regarding motor block, hemodynamic parameters, and neonatal outcomes. CONCLUSION: We conclude that clonidine in low doses is a useful adjuvant to local anesthetics for epidural labor analgesia and a good alternative to opioids.

Cochlear implantation and cardiac associations.

INTRODUCTION: Cochlear implantation is a safe surgery for restoration of hearing in profoundly deaf candidates. Profound deafness may at times, manifest as a part of a syndrome associated with cardiac anomalies. Cardiac co-morbidities may influence cochlear implantation in a spectrum of ways from minor intra operative issues to major life threatening complications. Issues related to pre operative, intra operative and post operative care needs to be addressed by an efficient in house cardiologist. OBJECTIVES: Our retrospective study was aimed at analyzing the various cardiac co-morbidities encountered in 30 out of 500 cochlear implantees over a period of 14 years (July 1999-June 2012). This study was focused on developing a profile of cardiac complications influencing cochlear implantation and suggests a protocol for management of various cardiac issues related to cochlear implantation. Our article also reflects the cardiologist's perspective of peri-operative care to be given during cochlear implantation. Relevant literature has been reviewed. METHODS: Case series of 30 profoundly deaf children (below 12 years) who had associated cardiac problems and underwent cochlear implantation in our institution were included in our study. Overall cardiac disease was identified in 30 out of 500 implantees (16.6%) in our experience. The cardiac disease can be categorized into 3 groups: candidates with isolated Patent Ductus Arteriosus (PDA) as Group A (8/30), candidates with syndrome and other anomalies with PDA association as Group B (18/30), and candidates with syndromes without PDA association as Group C (4/30). RESULTS: The overall incidence of cardiac problems in profoundly deaf candidates is identified. Descriptive profile of the same has been created and appropriate management for the same described. CONCLUSIONS: A protocol for management of cardiac co-morbidities influencing cochlear implantation has been designed and detailed insight for the optimal management of these issues has been discussed with cardiologist's perspective.